Reynold Spector

Use of hemoperfusion for treatment of theophylline intoxication

We review our experience in the management of patients with plasma theophylline concentrations of 30 micrograms/ml or greater. Over a two-and-a-half-year period, 22 patients (Group 1) had plasma theophylline concentrations of 37 +/- 1 micrograms/ml (mean +/- SE) and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death). Six patients (Group 2) took overdoses of theophylline (92 +/- 12 micrograms/ml) and one died. Eight patients (Group 3) were iatrogenically intoxicated (48 +/- 6 micrograms/ml) and three died. Six patients from Groups 2 and 3 underwent hemoperfusion and did well, except for one patient, in whom seizures developed before hemoperfusion was initiated. We conclude from this experience that charcoal hemoperfusion is a useful procedure for the treatment of theophylline intoxication because of: (1) the serious morbidity and mortality of theophylline intoxication, (2) the prevention of complications with hemoperfusion, and (3) the relative safety of the procedure. We provide tentative guidelines for the initiation of hemoperfusion for the treatment of theophylline intoxication.

VITAMIN B6 TRANSPORT IN THE CENTRAL NERVOUS SYSTEM: IN VIVO STUDIES

Abstract— The total concentrations of vitamin B6 (B6) in plasma, choroid plexus, CSF and brain of adult New Zealand white rabbits, measured fluorometrically, were 0.30, 15.10, 0.39 and 8.90μmol/l or kg respectively. The mechanisms by which B6 enters and leaves brain, choroid plexus and CSF were investigated by injecting [3H]pyridoxine (PIN) intravenously, intraventricularly and intraarterially. [3H]PIN, with or without unlabelled PIN, was infused intravenously at a constant rate into conscious rabbits. At 150 min, [3H]B6 readily entered CSF, choroid plexus and brain. The addition of 0.5 mmol/kg carrier PIN to the infusion solution depressed the relative entry of [3H]B6 into CSF, choroid plexus and brain by about 80%. After intraventricular injection, [3H]PIN readily entered brain from CSF. The intraventricular injection of carrier PIN with [3H]PIN decreased the amount of [3H]B6 in brain and also decreased the percentage of [3H]B6 in CSF and brain that was phosphorylated. During one pass through the cerebral circulation, [3H]PIN (1 μm) was cleared from the circulation no more rapidly than mannitol. These results were interpreted as showing that the entry of B6 from blood into CSF and presumably the extracellular space of brain and thence into brain cells involves one or more saturable transport and/or metabolic steps.

Vitamin B6 transport in the central nervous system: in vitro studies.

Abstract— The transport into and release of tritium labeled vitamin B6 ([3H]B6) from rabbit brain slices and isolated choroid plexuses were studied. In vitro, both brain slices and choroid plexus concentrated [3H]B6 by an energy dependent uptake system when [3H]pyridoxine (PIN) was added to the incubation medium. Most of the [3H] within the tissues was phosphorylated [3H]B6. In each tissue, the nonphosphorylated vitamers inhibited the uptake of [3H]PIN from the medium significantly more than the phosphorylated vitamers. The concentrations of the nonphosphorylated B6 vitamers necessary to inhibit brain and choroid plexus uptake of [3H]PIN from the medium by 50% were approx 0.4 μm and 5–10μm respectively after a 30 min incubation. Both brain slices and choroid plexus readily released (46 and 56% respectively in 30 min) previously accumulated [3H]B6 into artificial CSF. However, brain slices released only nonphosphorylated [3H]B6, whereas the choroid plexus released predominantly phosphorylated [3H]B6. Addition of unlabeled PIN to the release media significantly increased the percentage of [3H]B6 released by both brain slices and choroid plexus. The results of these in vitro studies provide evidence that: (1) both brain slices and chloroid plexus possess specific uptake and release mechanisms for B6, and (2) these mechanisms tend to regulate intracellular B6 levels. These studies also suggest that the choroid plexus serves as a locus for the transfer of B6 from blood to CSF and is the source of most of the phosphorylated B6 in CSF.

Therapeutic Use of Albumin: 2

It has previously been shown that albumin costs in a Veterans Administration Hospital constituted a large portion of the pharmacy drug budget and that much albumin was prescribed inappropriately. Therefore, a program of education and use monitoring was instituted to improve understanding and prescribing of this product. Inappropriate use declined from 41% to 26% of total albumin units and, more dramatically, total cost of albumin used had decreased by 90% one year after this program was initiated. Projected yearly savings from decreased use was more than

The origin of myo-inositol in brain, cerebrospinal fluid and choroid plexus

85,000. These results demonstrate that such a program can promote more appropriate use of albumin and effect a cost savings for hospitals.

The Effect of Dietary Protein on the Clearance of Allopurinol and Oxypurinol

UNBOUND myo-inositol (inositol) is present in brain, CSF and choroid plexus at concentrations higher than in plasma (SP~CTOR & LORENZO, 1975). In fasted rabbits, 68, 21. and 3% of the total unbound inositol in CP, CSF and brain, respectively, entered these structures from the plasma during an 18 h period (SPECTOR & LORENZO, 1975). The transport system for inositol from plasma into CP, CSF and brain could be saturated by increasing the plasma concentration of inositol; a locus of the inositol transport system appeared to be the CP (SPECTOR & LOR-

THE SPECIFICITY AND SULFHYDRYL SENSITIVITY OF THE INOSITOL TRANSPORT SYSTEM OF THE CENTRAL NERVOUS SYSTEM

A decrease in dietary protein is known to depress renal plasma flow and creatinine clearance. Using a randomized crossover design, we investigated the pharmacokinetics of allopurinol and its principal metabolite, oxypurinol, after oral administration of 600 mg of allopurinol in six normal subjects receiving a high-protein (268 g per day) or low-protein (19 g per day) diet. For allopurinol, the area under the curve of plasma concentration versus time increased by a factor of 1.45 (P less than 0.02), the renal clearance decreased by 28 per cent (P less than 0.02), and the ratio of the clearance of allopurinol to that of creatinine (fractional excretion) was unchanged between the low-protein and high-protein diets. For oxypurinol, the area under the curve increased nearly three-fold (P less than 0.02), the renal clearance decreased by 64 per cent (P less than 0.02), the fractional excretion decreased by 49 per cent (P less than 0.02), and the plasma oxypurinol half-life increased nearly threefold from 17.3 +/- 1.5 (mean +/- S.E.M.) to 49.9 +/- 2.9 hours (P less than 0.02) during the low-protein diet, as compared with the high-protein diet. We conclude that with the low-protein diet, the absorption, metabolism, and excretion of allopurinol were minimally altered but the total-body clearance of oxypurinol was greatly reduced because of a large increase in the net renal tubular reabsorption of oxypurinol.

Identification of dihydrofolate reductase in rabbit brain

Abstract— The transport of two cyclohexitol stereoisomers, myo‐inositol (inositol) and scyllo‐inositol (scyllitol), from blood into the CNS in vivo and into the choroid plexus in vitro was studied. In vitro, the uptake of [3H]scyllitol or [3H]inositol by choroid plexuses, isolated from rabbits and incubated in artificial CSF, was measured. Both scyllitol and inositol inhibited [3H]scyllitol or [3H]inositol accumulation by the choroid plexus. Inositol competitively inhibited [3H]scyllitol accumulation and both isomers had a comparable affinity (Kt= 0.1 mm) for the single cyclohexitol accumulation system. The other 6 stereoisomers tested had an order of magnitude less affinity for the cyclohexitol accumulation system of choroid plexus. Thiol reagents that penetrate cells inhibited inositol accumulation by choroid plexus more effectively than nonpenetrating thiol reagents. In vivo, in unanesthetized rabbits. the transport of unmetabolized [3H]inositol from blood into CSF, choroid plexus and brain was readily saturated by increasing the plasma levels of myo‐inositol but not by the stereoisomer d‐chiroinositol. Similarly, the transport of unmetabolized [3H]scyllitol into CSF, brain and choroid plexus was readily saturated by increasing the plasma levels of myo‐inositol. Beside documenting the stereospecificity and thiol reagent sensitivity of the inositol transport mechanism of the choroid plexus, these results provide further evidence that the choroid plexus is a locus for cyclohexitol transport between blood and CSF. Moreover, they show that scyllitol, which, like inositol, is present at a higher concentration in brain than plasma, can be transported from blood into CSF and brain by the same system that transports inositol.

Ascorbic acid transport by a clonal line of pheochromocytoma cells.

Abstract After partial purification, rabbit brain extracts were assayed for dihydrofolate reductase by spectrophometric, radiochemical and methotrexate binding assays. By these assays, the specific activity of rabbit brain dihydrofolate reductase was about 15 per cent that of liver. Both rabbit liver and brain dihydrofolate reductase activities were abolished by methotrexate and had comparable K m (3 μM), pH maxima (4.8), and cofactor requirements (NADPH). In vivo , a small percentage of [ 3 H]folic acid was reduced to [ 3 H]methyltetrahydrofolate when injected into the left lateral ventricle. Thus, both in vitro and in vivo , the central nervous system has the ability to reduce oxidized folates.

A rapid method for the determination of salicylate binding by the use of ultrafilters

A clonal line of rat pheochromocytoma cells was used as a model of noradrenergic tissue to study ascorbic acid transport. These cells were used because, like sympathetic neurons, they synthesize large amounts of noradrenaline in the presence of ascorbate, they respond to nerve growth factor with the production of neurites and they release, store and take up catecholamines. In these cells, both with and without nerve growth factor (NGF) treatment, [14C]ascorbic acid was concentrated by a stereospecific saturable, energy dependent transport system that could be described by a Michaelis-Menten transport model. The Kt and Vmax for ascorbic acid were approximately 0.03 mM and 0.3 nmole per min per mg protein respectively for both untreated and NGF-treated cells. The ability of the cells to concentrate ascorbic acid was not due to intracellular binding. Cells untreated with NGF and loaded with [14C]ascorbic acid to a concentration of 5.6 nmoles per mg protein retained only 6% of the initial intracellular [14C]ascorbic acid after the 24 h in normal growth medium. Thus, although pheochromocytoma cells contain an ascorbate concentrating system, optimal production of noradrenaline requires ascorbate in the medium.